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HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts
Heat shock protein 90 (HSP90) that is ubiquitously expressed in various tissues, is recognized to be a major molecular chaperone. We have previously reported that prostaglandin F(2α) (PGF(2α)), a potent bone remodeling mediator, stimulates the synthesis of interleukin-6 (IL-6) through p44/p42 mitoge...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438147/ https://www.ncbi.nlm.nih.gov/pubmed/28542188 http://dx.doi.org/10.1371/journal.pone.0177878 |
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author | Fujita, Kazuhiko Tokuda, Haruhiko Kuroyanagi, Gen Yamamoto, Naohiro Kainuma, Shingo Kawabata, Tetsu Sakai, Go Matsushima-Nishiwaki, Rie Kozawa, Osamu Otsuka, Takanobu |
author_facet | Fujita, Kazuhiko Tokuda, Haruhiko Kuroyanagi, Gen Yamamoto, Naohiro Kainuma, Shingo Kawabata, Tetsu Sakai, Go Matsushima-Nishiwaki, Rie Kozawa, Osamu Otsuka, Takanobu |
author_sort | Fujita, Kazuhiko |
collection | PubMed |
description | Heat shock protein 90 (HSP90) that is ubiquitously expressed in various tissues, is recognized to be a major molecular chaperone. We have previously reported that prostaglandin F(2α) (PGF(2α)), a potent bone remodeling mediator, stimulates the synthesis of interleukin-6 (IL-6) through p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that Rho-kinase acts at a point upstream of p38 MAP kinase. In the present study, we investigated the involvement of HSP90 in the PGF(2α)-stimulated IL-6 synthesis and the underlying mechanism in MC3T3-E1 cells. Geldanamycin, an inhibitor of HSP90, significantly amplified both the PGF(2α)-stimulated IL-6 release and the mRNA expression levels. In addition, other HSP90 inhibitors, 17-allylamino-17demethoxy-geldanamycin (17-AAG) and 17-dimethylamino-ethylamino-17-demethoxy-geldanamycin (17-DMAG) and onalespib, enhanced the PGF(2α)-stimulated IL-6 release. Geldanamycin, 17-AAG and onalespib markedly strengthened the PGF(2α)-induced phosphorylation of p38 MAP kinase. Geldanamycin and 17-AAG did not affect the PGF(2α)-induced phosphorylation of p44/p42 MAP kinase and myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase, and the protein levels of RhoA and Rho-kinase. In addition, HSP90-siRNA enhanced the PGF(2α)-induced phosphorylation of p38 MAP kinase. Furthermore, SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by geldanamycin, 17-AAG or 17-DMAG of the PGF(2α)-stimulated IL-6 release. Our results strongly suggest that HSP90 negatively regulates the PGF(2α)-stimulated IL-6 synthesis in osteoblasts, and that the effect of HSP90 is exerted through regulating p38 MAP kinase activation. |
format | Online Article Text |
id | pubmed-5438147 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-54381472017-05-27 HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts Fujita, Kazuhiko Tokuda, Haruhiko Kuroyanagi, Gen Yamamoto, Naohiro Kainuma, Shingo Kawabata, Tetsu Sakai, Go Matsushima-Nishiwaki, Rie Kozawa, Osamu Otsuka, Takanobu PLoS One Research Article Heat shock protein 90 (HSP90) that is ubiquitously expressed in various tissues, is recognized to be a major molecular chaperone. We have previously reported that prostaglandin F(2α) (PGF(2α)), a potent bone remodeling mediator, stimulates the synthesis of interleukin-6 (IL-6) through p44/p42 mitogen-activated protein (MAP) kinase and p38 MAP kinase in osteoblast-like MC3T3-E1 cells, and that Rho-kinase acts at a point upstream of p38 MAP kinase. In the present study, we investigated the involvement of HSP90 in the PGF(2α)-stimulated IL-6 synthesis and the underlying mechanism in MC3T3-E1 cells. Geldanamycin, an inhibitor of HSP90, significantly amplified both the PGF(2α)-stimulated IL-6 release and the mRNA expression levels. In addition, other HSP90 inhibitors, 17-allylamino-17demethoxy-geldanamycin (17-AAG) and 17-dimethylamino-ethylamino-17-demethoxy-geldanamycin (17-DMAG) and onalespib, enhanced the PGF(2α)-stimulated IL-6 release. Geldanamycin, 17-AAG and onalespib markedly strengthened the PGF(2α)-induced phosphorylation of p38 MAP kinase. Geldanamycin and 17-AAG did not affect the PGF(2α)-induced phosphorylation of p44/p42 MAP kinase and myosin phosphatase targeting subunit (MYPT-1), a substrate of Rho-kinase, and the protein levels of RhoA and Rho-kinase. In addition, HSP90-siRNA enhanced the PGF(2α)-induced phosphorylation of p38 MAP kinase. Furthermore, SB203580, an inhibitor of p38 MAP kinase, significantly suppressed the amplification by geldanamycin, 17-AAG or 17-DMAG of the PGF(2α)-stimulated IL-6 release. Our results strongly suggest that HSP90 negatively regulates the PGF(2α)-stimulated IL-6 synthesis in osteoblasts, and that the effect of HSP90 is exerted through regulating p38 MAP kinase activation. Public Library of Science 2017-05-19 /pmc/articles/PMC5438147/ /pubmed/28542188 http://dx.doi.org/10.1371/journal.pone.0177878 Text en © 2017 Fujita et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Fujita, Kazuhiko Tokuda, Haruhiko Kuroyanagi, Gen Yamamoto, Naohiro Kainuma, Shingo Kawabata, Tetsu Sakai, Go Matsushima-Nishiwaki, Rie Kozawa, Osamu Otsuka, Takanobu HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts |
title | HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts |
title_full | HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts |
title_fullStr | HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts |
title_full_unstemmed | HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts |
title_short | HSP90 inhibitors potentiate PGF(2α)-induced IL-6 synthesis via p38 MAP kinase in osteoblasts |
title_sort | hsp90 inhibitors potentiate pgf(2α)-induced il-6 synthesis via p38 map kinase in osteoblasts |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5438147/ https://www.ncbi.nlm.nih.gov/pubmed/28542188 http://dx.doi.org/10.1371/journal.pone.0177878 |
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